Activation of multiple small GTPases in the Ras and Rho families promotes the proliferation and migration of non-small cell lung carcinoma (NSCLC) cells, which contributes to NSCLC tumorigenesis and metastasis. Surprisingly little is known about how small GTPases are activated in NSCLC cells to promote tumorigenesis and metastasis. Our research indicates that the unique guanine nucleotide exchange factor known as SmgGDS is a major regulator of small GTPase activity in NSCLC. SmgGDS uniquely activates multiple small GTPases in the Ras and Rho families. We previously reported that SmgGDS is expressed at high levels in NSCLC tumors and stimulates the proliferation and migration of NSCLC cells. We recently discovered that NSCLC cells express several forms of SmgGDS. Our results support the model that different forms of SmgGDS promote post-translational processing of the small GTPases K-Ras, Rac1, RhoA, Rap1A, and Rap1B. This model will be tested in the following aims. Aim1: Define the expression of different forms of SmgGDS in NSCLC tumors from patients and in NSCLC cell lines. Aim 2: Determine which form of SmgGDS and which of the small GTPases that interact with SmgGDS contribute the most to NSCLC cell proliferation, migration, tumorigenesis, and experimental metastasis. Aim 3: Characterize how different forms of SmgGDS regulate the activity, post-translational processing, and subcellular localization of different small GTPases in NSCLC. This research will define the unique ability of SmgGDS to regulate the activities of K-Ras, Rac1, RhoA, Rap1A, and Rap1A in NSCLC, and will help determine the therapeutic potential of these proteins in lung cancer.